Retinal metabolism in humans induces the formation of an unprecedented lipofuscin fluorophore 'pdA2E'.
Retinal metabolism in humans induces the formation of an unprecedented lipofuscin fluorophore 'pdA2E'.
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DOI：
10.1042/bj20140089
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发表时间：
2014-06
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通讯作者：
Yalin Wu;Qiu-xia Jin;Ke Yao;Junli Zhao;Jing-meng Chen;Xiaodan Wu;Lishe Gan;Jie Li;Xiaohui Song;Xin Liu;Xianhui Cai
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作者：
Yalin Wu;Qiu-xia Jin;Ke Yao;Junli Zhao;Jing-meng Chen;Xiaodan Wu;Lishe Gan;Jie Li;Xiaohui Song;Xin Liu;Xianhui Cai
RPE（视网膜色素上皮）中的有毒脂褐素与AMD（年龄相关性黄斑变性）或隐性Stargardt病患者的失明有关。在本研究中，我们确定了一种新的荧光脂褐素成分在人类和牛RPE。利用1D和2D NMR和MS，我们证实了这种色素的结构，并将其命名为pdA 2 E。它在492和342 nm处表现出最大吸收，并且对光催化异构化和氧化敏感。在AMD/隐性Stargardt病模型Abca 4（-/-）Rdh 8（-/-）（Abca 4编码ATP结合盒转运蛋白4，Rdh 8编码视黄醇脱氢酶8）小鼠的眼杯提取物中也检测到该荧光团。pdA 2 E在RPE细胞内的过量积累导致显著的细胞活力丧失和膜损伤。pdA 2 E的形成发生在atRAL（全反式-视黄醛）与过量乙醇胺在不存在乙酸的情况下反应时，并且该过程可能涉及三个atRAL分子的参与。我们的研究结果表明，内源性pdA 2 E可能作为一种敏化剂产生单线态氧和单线态氧淬灭剂，以及视网膜代谢的副产品，其完整的表征有利于了解生物合成途径，其中不利的RPE脂褐素成分的形式。
Toxic lipofuscin in the RPE (retinal pigment epithelium) is implicated in blindness in AMD (age-related macular degeneration) or recessive Stargardt's disease patients. In the present study, we identified a novel fluorescent lipofuscin component in human and bovine RPEs. Using 1D and 2D NMR and MS, we confirmed the structure of this pigment and called it pdA2E. It exhibits absorbance maxima at 492 and 342 nm, and is susceptible to photocatalytic isomerization and oxidation. This fluorophore was also detected in the eyecup extracts of Abca4(-/-)Rdh8(-/-) (Abca4 encodes ATP-binding cassette transporter 4 and Rdh8 encodes retinol dehydrogenase 8) mice, an AMD/recessive Stargardt's disease model. Excess amassing of pdA2E within RPE cells caused significant cell viability loss and membrane damage. The formation of pdA2E occurred when atRAL (all-trans-retinal) reacted with excess ethanolamine in the absence of acetic acid, and the process is likely to involve the participation of three atRAL molecules. Our findings suggest that endogenous pdA2E may serve as a sensitizer for yielding singlet oxygen and a singlet oxygen quencher, as well as a by-product of retinal metabolism, and its complete characterization facilitates the understanding of biosynthetic pathways by which adverse RPE lipofuscin constituents form.